The Importance of Dendritic Cells in Maintaining Immune Tolerance Cindy Audiger, M

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The Importance of Dendritic Cells in Maintaining Immune Tolerance Cindy Audiger, M. Jubayer Rahman, Tae Jin Yun, Kristin V. Tarbell and Sylvie Lesage This information is current as of October 1, 2021. J Immunol 2017; 198:2223-2231; ; doi: 10.4049/jimmunol.1601629 http://www.jimmunol.org/content/198/6/2223 Downloaded from References This article cites 166 articles, 73 of which you can access for free at: http://www.jimmunol.org/content/198/6/2223.full#ref-list-1

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The Importance of Dendritic Cells in Maintaining Immune Tolerance x { Cindy Audiger,*,†,1 M. Jubayer Rahman,‡,1 Tae Jin Yun, , Kristin V. Tarbell,‡ and Sylvie Lesage*,† Immune tolerance is necessary to prevent the immune specific depletion of CD11c+ cells (3). CD11c is an integrin system from reacting against self, and thus to avoid expressed at high levels by DCs and at much lower levels by the development of autoimmune diseases. In this review, many cellular subsets, namely neutrophils, macrophages, NK we discuss key findings that position dendritic cells cells, as well as activated monocytes and T cells. Selective + (DCs) as critical modulators of both thymic and periph- depletion of CD11c cells induces an increase in effector Th1 eral immune tolerance. Although DCs are important for and Th17 cells and strong autoimmune symptoms, such as lymphadenopathy, splenomegaly, and infiltration of non- inducing both immunity and tolerance, increased auto- Downloaded from immunity associated with decreased DCs suggests their lymphoid organs (3–5). Elimination of DCs in mice thus is nonredundant role in tolerance induction. DC-mediated sufficient to break immune tolerance and lead to autoimmune T cell immune tolerance is an active process that is influ- pathology, suggesting that DCs play a central role in the enced by genetic variants, environmental signals, as well maintenance of immune tolerance. Notably, these findings were recently confirmed in a model that permits more selec- as the nature of the specific DC subset presenting Ag to tive elimination of DCs. Indeed, within the hematopoietic http://www.jimmunol.org/ T cells. Answering the many open questions with regard system, the Zbtb46 transcription factor is exclusively expressed to the role of DCs in immune tolerance could lead to the in DCs (6). The specific depletion of DCs in Zbtb46–diph- development of novel therapies for the prevention of au- theria toxin receptor (DTR) adult mice via diphtheria toxin toimmune diseases. The Journal of Immunology, 2017, injection causes lymphoangiogenesis and myeloproliferative 198: 2223–2231. disorders, thus confirming the importance of DCs in the maintenance of immune tolerance (7, 8). Interestingly, the ntigen-presenting cells, namely B cells, macrophages, autoimmune pathology was less severe in the Zbtb46-DTR and dendritic cells (DCs), initiate both protective mice when compared with the CD11c-DTA mice, possibly A and autoimmune T cell responses, and DCs bear the because of either the more selective nature of the Zbtb46-DTR by guest on October 1, 2021 highest Ag presentation potential, as shown by stronger in- model or the timing of DC deletion. The CD11c-DTA model duction of naive T cell activation (1). DCs play a nonre- continuously deletes DCs from early development, but the dundant role in the initiation of immune responses and the deletion of DCs in Zbtb46-DTR mice is transiently in- control of some pathogens. For instance, IRF8 mutations in duced in adult mice. Nevertheless, both experimental set- humans cause defects in DCs, resulting in opportunistic in- tings show that elimination of DCs in mice is sufficient to fections and an increase in anergic T cells (2). Additionally, break immune tolerance and lead to autoimmune pathology, DCs also play a key role in maintaining immune tolerance, as suggesting that DCs play a central role in the maintenance of we discuss in this review. immune tolerance. The importance of DCs in maintaining immune tolerance If depletion of DCs leads to autoimmune phenotypes, one was shown by using mouse models to manipulate the number could postulate that increasing the prevalence of DCs would of DCs in vivo. For one, the CD11c–Cre/ROSA-diphtheria strengthen immune tolerance and prevent autoimmune disease toxin A (CD11c-DTA) transgenic mouse model allows for occurrence. To this effect, Flt3 ligand injection increases the

*Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, Que´bec and by Fondation Lucie-Besner. S.L. is supported by Fonds de Recherche en Quebec H1T 2M4, Canada; †De´partement de Microbiologie, Infectiologie et Immu- Sante´ du Que´bec, and by grants from the Natural Sciences and Engineering Research nologie, Universite´ de Montre´al, Montreal, Quebec H3C 3J7, Canada; ‡Immune Tol- Council and the Cancer Research Society. erance Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of T.J.Y. prepared the ﬁgures; C.A., M.J.R., K.V.T., and S.L. wrote the paper; all authors Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, x read and approved the manuscript. MD 20892; Laboratory of Cellular Physiology and Immunology, Clinical Research { Institute of Montreal, Montreal, Quebec H2W 1R7, Canada; and Division of Exper- Address correspondence and reprint requests to Dr. Sylvie Lesage, Research Center, imental Medicine, Department of Medicine, McGill University, Montreal, Quebec H3A Maisonneuve-Rosemont Hospital, 5415 l’Assomption Boulevard, Montreal, QC H1T 1A3, Canada 2M4, Canada. E-mail address: [email protected] 1C.A. and M.J.R. contributed equally to this work. Abbreviations used in this article: cDC, conventional DC; CD11c-DTA, CD11c–Cre/ ROSA-diphtheria toxin A; DC, dendritic cell; DTR, diphtheria toxin receptor; EAE, ORCIDs: 0000-0001-9087-9036 (C.A.); 0000-0002-0968-2795 (S.L.). experimental autoimmune encephalitis; GVHD, graft-versus-host disease; MHC-I, Received for publication September 19, 2016. Accepted for publication December 11, MHC class I; MHC-II, MHC class II; pDC, plasmacytoid DC; RTOC, reaggregate 2016. thymus organ culture; tol-DC, DC with tolerogenic properties; Treg, regulatory T cell.

M.J.R. and K.V.T. are supported by the intramural research programs of the National Ó Institute of Diabetes and Digestive and Kidney Diseases. C.A. is supported by a schol- Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 arship from the Montreal Diabetes Research Center in collaboration with Diabe`te

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601629 2224 BRIEF REVIEWS: DENDRITIC CELLS IN IMMUNE TOLERANCE proportion of DCs in vivo and prevents autoimmune diabetes ofsuperantigens,toinduceeffectivecentraltolerance(27). onset in NOD mice (9). However, a break in immune tol- In comparison with macrophages and B cells, only DCs were erance is observed in mouse models where DC number is able to induce negative selection of thymocytes in reaggre- increased by inhibiting DC apoptosis. Specifically, transgenic gate thymus organ cultures (RTOCs) (25), showing the dom- mice with CD11c promoter-driven p35, a caspase inhibi- inant role of DCs in central tolerance. More recently, it was tor that blocks apoptosis, present with an accumulation shown that DCs are not simply bystanders in the thymocyte of DCs in lymphoid organs over time (10). Consequently, selection process. They actively attract postpositive selection CD11c-p35 transgenic mice exhibit lymphocytic infiltration thymocytes by producing CCR4 ligand to facilitate the neg- in nonlymphoid organs, activation of both T and B cells, and ative selection process (28). Interestingly, and likely due to the production of anti-DNA Ab (10). Also, DC-specific knock- experimental challenges associated with separating central and out of Bim decreases DC apoptosis, which leads to an increase peripheral tolerance processes, the general outcome of a defect in DCs and results in inflammation (11). Therefore, depending in DC-mediated central tolerance on the potential develop- on the context, an increase in the number of DCs can either ment of an autoimmune phenotype has yet to be clearly de- increase or decrease T cell tolerance. This is perhaps due to fined. distinct impacts on the DC phenotype, such that expansion of Although all thymic DCs contribute to central tolerance, DCs either by stimulating hematopoiesis or by blocking DC they do so through different means (Fig. 1). Three thymic DC apoptosis may yield different outcomes in the maintenance subsets contribute to central tolerance, namely resident DCs 2 2 of immune tolerance. Still, because DCs are capable of both (CD8a+SIRPa ), migratory DCs (CD8a CD11b+SIRPa+), immunity and tolerance, manipulation of numbers alone and plasmacytoid DCs (pDCs; CD11cintCD45RAint) (29– Downloaded from may not be a consistent way to alter the balance of immunity 32). Resident DCs that develop from thymic lymphoid pre- and tolerance. cursors are the most abundant subset and are primarily Induction of stable tolerogenic DCs could provide a pow- localized in the medulla (29, 31, 33, 34). They contribute to erful platform for Ag-specific treatment of autoimmune dis- the elimination of autoreactive thymocytes by presenting a eases. In vitro protocols to induce DCs with tolerogenic wide array of self-antigens, and by cross-presenting both properties (tol-DCs) include the differentiation of DC pre- blood-derived Ag and tissue-specific Ags from medullary http://www.jimmunol.org/ cursors in media complemented with agents such as dexa- thymic epithelial cells (35–37). Migratory SIRPa+ DCs also methasone, IL-10, or TGF-b (12). These tol-DCs can then be contribute to central tolerance. They develop in the periphery loaded with specific Ags and, upon injection in vivo, are ex- and, as shown in parabiosis experiments, migrate to the thy- pected to provide Ag-specific immune tolerance through mus via CCR2/a4 integrin where they mostly localize to the different means, such as by promoting Ag-specific regulatory corticomedullary junction to present peripheral self-antigens T cell (Treg) differentiation or by producing IDO and/or NO to developing thymocytes (34, 38, 39). pDCs also develop in (13). Various DC populations that facilitate immune toler- the periphery and use CCR9/a4 integrin signals to migrate to ance have also been identified in vivo (14). For example, the thymus and contribute to the maintenance of immune by guest on October 1, 2021 low + spleen CD11c CD45RB DCs induce Ag-specific differ- tolerance (32). Interestingly, in RTOC experiments, pDCs entiation of Tregs via Ag presentation and IL-10 production were shown to only minimally contribute to the induction of low high low (15, 16). Additionally, CD11c CD11b I-A DCs create negative selection (25). The reason for this discrepancy is not a tolerogenic environment by secreting high levels of IL-10 clear, but it may be due to the different localization of cells in and NO (17). Therefore, understanding the mechanisms by RTOCs. Still, all of the DC subsets contribute to immune which DCs can induce and maintain both central and pe- tolerance by presenting self-antigens and inducing negative ripheral immune tolerance may inform treatments for auto- selection of developing thymocytes that present with a high immunity. In this review, we discuss the mechanisms by affinity to self-ligands. Whereas pDCs and migratory DCs which DC subsets can induce steady-state immune tolerance, specialize in the presentation of peripheral Ags, resident DCs and how an inflammatory/autoimmune disease context can provide immature T cells with a distinct self-antigenic rep- change DC-mediated tolerance. ertoire. Additionally, although thymic resident and migratory conventional DCs (cDCs) can uptake MHC class I (MHC-I) Thymic tolerance and MHC-II from thymic epithelial cells in a cell contact– The process of central tolerance in the thymus eliminates dependent manner, this process is dependent on the PI3K potentially autoreactive thymocytes by negative selection and pathway only for CD8a+ resident cDCs (40), further sup- promotes T cell differentiation into various Treg subsets via porting the view that each DC subset provides a nonredun- additional selection processes (18–22). Central tolerance is, in dant role in Ag presentation to T cells and in the maintenance fact, highly dependent on the presentation of self-antigens to of central tolerance. T cells by both thymic epithelial cells and APCs (23–25). In addition to inducing negative selection, thymic DCs are Early work showed that MHC expression on thymic bone also important for the selection of natural Tregs during thy- marrow–derived APCs contributes to central tolerance in- mocyte differentiation. Proietto et al. (41) constructed mixed duction (26). Among these APCs, DCs clearly contribute to bone marrow chimeric mice, with T cells specific to a given 2 2 elimination of maturing autoreactive thymocytes, as DC- Ag (from OT-II.Rag2 / mice) and DCs as the only source specific expression of MHC class II (MHC-II) I-E is suffi- of APCs presenting this Ag (from CD11c-OVA mice). In cient to negatively select thymocytes specific for endoge- these mice, DCs successfully induced the differentiation of nous superantigens in a manner comparable to that of mice natural Ag-specific Tregs in the thymus. Specifically, both expressing the I-Ea transgene on all APCs (27). MHC ex- resident and migratory DCs, but not pDCs, are able to induce pression on DCs thus appears sufficient, at least in the context Tregs in vitro (25, 41, 42), but the mechanisms by which they The Journal of Immunology 2225

that requires TCR signaling (45). T cell clonal deletion is mediated by the activation of Fas-, Bim-, or TNF-dependent apoptosis and inhibition of NF-kB signaling (46–48). Many DC factors contribute to the balance of tolerance and immunity, including maturation states defined by their gene signature, and the level of Ag presentation; therefore, it is necessary to understand the conditions under which DCs remain immature or become activated (37, 49, 50). Steady-state DCs that normally express low levels of DC maturation markers and promote tolerance induction are termed immature DCs (51). Once activated by pathogen or damage-associated molecular patterns, DCs turn on different metabolic, cellular, and gene transcription programs that initiate increased DC migration out of peripheral tissue into draining lymph nodes where Ag presentation to T cells occurs (52–54). DC maturation is marked by increased expression of molecules relevant for T cell activation, including MHC-II, costimulatory proteins such as CD40, CD80/CD86, and inflammatory cytokines or chemokines (55–57). However, Downloaded from functional capacity of DCs to induce T cell activation does not always directly correlate with common maturation markers, in part because Tregs use some of the same signals, including CD80/CD86 (58–60). Therefore, tolerogenic and immunogenic DCs should ideally be defined based on the signals they give to conventional T cells or Tregs (37). http://www.jimmunol.org/ Steady-state DCs are exposed to commensal microorganisms FIGURE 1. DC-mediated central tolerance. Migratory CD11b+CCR2+ and other tonic inflammatory signals that can induce the DCs and CCR9+ pDCs migrate from periphery to the thymic cortex and expression of maturation markers at low levels, which are induce tolerance to peripheral self-antigens by inducing apoptosis of autore- not sufficient to break self-tolerance in most individuals. + active thymocytes. Migratory DCs also promote Treg differentiation. CD8a The ability of steady-state DCs to remain in an immature/ resident DCs induce apoptosis of thymocytes reactive to self-antigens and promote Treg differentiation and survival. nonactivated form likely depends on the timing, dose, and signal strength of the factors interacting with DCs. Steady-state DC migration is associated with considerable transcriptional by guest on October 1, 2021 induce Tregs are distinct (Fig. 1). Resident DCs promote changes, suggesting that immunoregulatory function of steady- Treg survival via their expression of CD70, whereas CD70- state DCs is an active process (37). Indeed, regulators such as deficient migratory DCs effectively induce Tregs through an A20 can modulate NF-kB signaling and contribute to main- undefined pathway (42). However, the capacity to induce taining tolerance (61–64). UpregulationinDCsofIDOsynthesis, Tregs is not restricted to DCs. When high concentrations of a rate-limiting enzyme of tryptophan catabolism, contributes to self-antigens are present, Tregs can differentiate in RTOCs tolerance by depleting tryptophan and causing apoptosis of ef- devoid of APCs, suggesting that epithelial cells can sometimes fector T cells (65–67). Negative costimulation via CTLA4-CD80/ induce Tregs (25). As such, thymic Treg numbers are normal CD86 or PD-1–PD-L1/PD-L2 is also implicated in the induction in mice that only express MHC-II on epithelial cells (43). of tolerance, but these proteins display minimal expression on Therefore, both thymic epithelial cells and DCs play an active steady-state DCs, suggesting that these inhibitory signals may be role in the induction of central tolerance through both the more important for dampening activation in the context of in- elimination of potentially autoreactive thymocytes and in fa- flammatory signals (68–70). cilitating the generation of Tregs. As thymic epithelial cells Peripheral DCs are subdivided into functional subsets with and DCs bear distinct immunopeptidomes, one can presume various locations and roles in both immunity and tolerance, that these roles are not fully redundant. Indeed, both have the namely pDCs, monocyte-derived DC (moDCs), and cDCs. capacity to uptake Ags from different sources and exploit The latter are further subdivided into two populations, that different proteolytic pathways resulting in distinct peptide is, CD8a+/CD103+ and CD11b+ (71). moDCs (CD11c+ repertoires, with each contributing toward effective induction CD11bhighMHC-II+) are usually inflammatory and separated of central tolerance (20). from the cDCs by higher CD11b expression and lack of cDC- specific markers such as CD4 and DCIR2 (54, 72). Because DC-mediated peripheral tolerance mechanisms many studies do no separate cDCs from moDCs in their Although thymic selection efficiently eliminates many self- analyses, it is not yet clear whether moDCs can contribute to reactive T cells, some remain and must be kept in check tolerance induction, whereas strong evidence supports a clear with additional peripheral tolerance mechanisms to avoid role for both cDCs and pDCs in the maintenance of immune autoimmunity. In the absence of inflammation, DCs can tolerance. present self-antigens to T cells, providing transient T cell cDCs prime T cells via Ag presentation and other signals, activation that can lead to either anergy or deletion of these leading to immunogenicity or tolerance (49, 70, 73–75). T cells (44). DC-mediated tolerance is thus an active process Delivering Ag to particular cDC subsets via chimeric Abs 2226 BRIEF REVIEWS: DENDRITIC CELLS IN IMMUNE TOLERANCE specific for lectin cell surface receptors can elucidate the role pDCs are a specialized subset of DCs that rapidly make a large of these subsets in T cell tolerance induction (Fig. 2). CD8a+ amount of type 1 IFN in response to signals such as viral in- cDCs express DEC205 and are located in the T cell zone in fections (Fig. 2). In the steady-state, pDCs express very low the spleen where they can cross-present exogenous Ag to levels of MHC-II and costimulatory molecules and may con- CD8+ T cells via MHC-I. DCIR2, another DC lectin re- tribute to T cell unresponsiveness. Although pDCs are not as ceptor, is expressed by murine CD11b+ cDCs and some hu- efficient as cDCs for Ag presentation to T cells, pDCs can man DCs (76–78) In mice, CD11b+DCIR2+ DCs located in upregulate MHC-II molecules on their surface and migrate to the red pulp and marginal zone area of the spleen can migrate the T cell area and induce T cell proliferation and Treg gen- to the edge of the T cell zone where they primarily stimulate eration (93, 94). Activated pDCs can have enhanced MHC-II CD4+ T cells (79–82). Both DEC205 and DCIR2 are effi- expression (95, 96), allowing for prolonged T cell activation ciently internalized upon receptor–ligand interaction, and that may contribute to Treg development, as increased MHC-II these receptors are directed to endosomal/lysosomal com- on pDCs is required for Treg homeostasis (97). Type 1 IFN and partments for Ag presentation (79, 83). In mice that have IL-10 produced by pDCs may also contribute to Treg genera- been challenged with anti-DEC205– or anti-DCIR2–medi- tion (98). pDCs can produce IDO and express PD-L1 that ated Ag delivery to cDCs during steady-state, Ag-specific correlate with an increased Treg frequency (99, 100). Tolero- T cells are rapidly deleted and the remaining Ag-specific genic pDCs have been reported in many inflammatory disorders, T cells become unresponsive upon in vitro stimulation (65, including acute graft-versus-host disease (GVHD), autoimmune 75, 79). Some studies have proposed that natural ligands for arthritis, and oral tolerance, where they promote tolerance by DEC205 such as apoptotic, necrotic materials or CpG may modulating Treg function or by maintaining Ag-specific T cell Downloaded from stimulate CD8a+ cDCs and possibly contribute to their tolerance (101–103). maturation (84, 85). Still, many lectins can impart matura- The local environment also plays an important role in mod- tion or inhibitory signals upon binding ligand or Ab (86, 87), ulating DC tolerogenic function. For example, migratory dermal and recent evidence points to DCIR2 in providing a negative DCs and Langerhans cells present in both the skin and skin- signal to cDCs, further adding to the role of DCIR2 in the draining lymph nodes appear to play a central role in Treg cDC-mediated maintenance of steady-state tolerance (88). differentiation. DCs in skin-draining lymph nodes are particu- http://www.jimmunol.org/ cDCs not only induce tolerance by deleting Ag-specific larly effective at inducing Tregs, as Tregs converted from naive T cells or by inducing anergy, but they can also promote CD4 T cells display enhanced immunoregulatory properties Treg differentiation or function (Fig. 2). Whereas CD8a+ when isolated from the skin-draining lymph nodes rather than the cDCs are more efficient in providing TGF-b for de novo spleen of mice (104). In mice where langerin+ migratory DCs are Foxp3+ Treg generation, likely potentiated by BLTA expres- depleted using diphtheria toxin injections in Lang-DTR trans- sion (89), CD11b+ cDCs enhance activation and proliferation genic mice, anti-DEC205–mediated Ag-specific delivery to DCs of existing CD4+Foxp3+ Tregs (90). Interestingly, Tregs play isnolongerabletoinduceAg-specificTregsinthespleenand a very important role in steady-state cDC-mediated tolerance. skin-draining lymph nodes and results in a loss of immune by guest on October 1, 2021 + Depletion of Foxp3 Tregs increases cDC numbers as well as tolerance (105, 106). Importantly, langerin+ migratory DCs the surface expression of costimulatory molecules, resulting in may, in fact, uniquely contribute to the induction of Tregs and enhanced T cell responses (91). This strongly suggests that the maintenance of peripheral tolerance, as the specific depletion Tregs also contribute to peripheral tolerance by maintaining of langerin+ DCs has no effect on the initiation of antiviral re- cDCs in the immature state (91, 92). sponses (107). This latter finding suggests that specific DC subsets found in unique environments may have specialized roles in immune tolerance. Further investigation of the role of langerin+ DCs in the modulation of various immune responses is needed to clarify their contribution in pathogenic settings. DCs found in the gut-associated lymphoid tissues can also promote immune tolerance. As in the skin, CD103+ DCs in the gut tissue express high levels of the enzyme aldehyde de- hydrogenase, which converts vitamin A into retinoic acid, which in turn promotes the conversion of naive T cells into Tregs (108, 109). A second mechanism by which gut DCs induce tolerance is through the production of IDO, which itself facilitates induction of Tregs (110). In fact, selective 2 elimination of CD103+CD11b DCs results in a decrease in IDO levels and an increased susceptibility to dextran sodium sulfate–induced colitis (111). Finally, CD103+CD11b+ DCs also significantly contribute to immune tolerance through the expression of acyloxyacyl hydrolase, an enzyme able to inac- tivate LPS and thus to prevent effective TLR4 activation that induces the differentiation of naive T cells into effector Th17 cells (112). Collectively, these data support the view that DCs FIGURE 2. DC-mediated peripheral tolerance. cDCs and pDCs induce tolerance by promoting Treg differentiation or function. cDCs can also induce found in the gut microenvironment are geared to promote peripheral tolerance by inducing T cell anergy or T cell deletion. In inflam- immune tolerance, likely because of the perpetual exposure to matory conditions, cDCs and pDCs promote T cell activation. microflora and to food Ags (113). The Journal of Immunology 2227

How do DCs maintain/adjust tolerance against self-antigens modulation of IFN-A receptor (137, 138). However, NOD in the context of inflammatory signals? Although activated DCs and other APCs are hyperactive due to increased proin- DCs acquire strong phenotypic changes linked with enhanced flammatory signals resulting from a defect in NF-kB regulation effector T cell function and inflammatory cytokine produc- that enhances Ag presentation to CD8 T cells (139, 140). tion, DCs can also exert regulatory function under inflam- Therefore, the balance of different types of inflammatory signal matory situations. For example, pDCs promote persistence of is likely important for autoimmune pathogenesis, and type 1 viral infection in the liver (114). Even under strong activation IFN and IL-1 signals can counterregulate each other (141–143). due to allergen exposure, pulmonary DCs can stimulate the IL-1 and increased NF-kB activation may be the dominant development of CD4+ T regulatory 1–like cells (115). Im- inflammatory signal for type 1 diabetes (144). Autoimmunity munoregulatory DCs in the context of infection have been may also lead to changes in DC costimulatory molecule ex- defined based on the net sum of inhibitory versus stimulatory pression. DCs from prediabetic NOD mice have increased signals. Induction of inhibitory molecules, including PD-1, CD40 expression that is dependent on adaptive immune cells. TGF-b, or IDO, and downregulation of costimulatory mol- Increased CD40 expression could be more indicative of in- ecules or cytokines are important correlates of regulatory DC flammation, as blocking CD40 signals blocks NOD autoim- function (116, 117). For example, upon infection with Lis- mune diabetes pathogenesis (145–148). teria monocytogenes, DCs induce both stimulatory and regu- The role of particular DC subsets in tolerance induction latory molecules (118). Infected DCs suppress T cell activity also differs in autoimmune contexts. Although both CD8a+ mainly by IL-10 and cyclooxygenase 2–mediated mechanisms DEC205+ and CD11b+DCIR2+ DCs are tolerogenic in (118, 119). In certain contexts, signals associated with in- normal mice, only the CD11b+DCIR2+ DCs are able to in- Downloaded from flammation, such as TLR2, TNF-a, and PG receptor, can duce CD4 tolerance in NOD mice (78). NOD mice have induce immunoregulatory DC phenotypes (118). In chronic fewer CD8a+ DCs in the spleen, and the function of this DC viral infection, DCs can become immunosuppressive, losing subset is altered; that is, the cross-presentation capacity of their surface expression of MHC-I and MHC-II and co- NOD DCs is reduced relative to CD8a+ DC from non– stimulatory molecules (120). DCs also upregulate PD-L1 autoimmune-prone mice (149). This significantly reduces during chronic viral infections such as HIV and hepatitis C the potential for cross-tolerance, a mechanism involved in http://www.jimmunol.org/ virus (121–123). PD-L1 interacts with PD-1 on T cells, maintaining immune tolerance (150). This more pathogenic which can induce T cell deletion and also increase Treg gen- role for CD8a+DEC205+ DCs in NOD mice was further eration and function by enhancing FOXP3 expression, in confirmed by the lack of diabetes development in NOD 2 2 humans (124). Batf3 / mice that cannot develop these cross-presenting DCs (151). NOD mice also exhibit an increased proportion DCs and autoimmune pathologies/diseases of recently described merocytic DCs (152, 153). This un- Autoimmune diseases occur, in part, because of changes in DC conventional DC subset is sufficient to break tolerance at function that result from genetic and environmental alterations steady-state (154). Additionally, the H2g7-specific MHC by guest on October 1, 2021 (125–127). Disruption of the tolerance network contributed by haplotype affects the spectrum of Ag presentation, which has each DC subset can promote autoreactive T cell responses and been proposed to contribute to autoimmune susceptibility pathology. Therefore, therapies targeting DCs may be effective (155). In experimental autoimmune encephalitis (EAE), a treatment for autoimmunity. Identifying the DC signaling mouse model of multiple sclerosis, the role of DCs for con- pathways that are altered in the context of autoimmunity and trolling immune tolerance was demonstrated with two com- that can interrupt T cell tolerance induction will help define the plementary approaches. The lack of MHC-II on APCs using signals that allow induction of stable tolerogenic DCs. In ad- MHC-II–deficient bone marrow chimeric mice reduced EAE dition to the pattern recognition receptors that sense danger symptoms and histopathology scores. Conversely, MHC-II signals, host-derived non–pathogen-associated chronic inflam- expression restricted to CD11c+ DCs is sufficient to induce matory signals are also playing a role in autoimmune pathology EAE pathophysiology in mice bearing myelin oligodendrocyte- (75, 128). DC function could be altered under this persistent specific T cells (156). pDCs are also important in regulating host-derived inflamed situation (Fig. 2). multiple sclerosis susceptibility, but their protective or detri- One critical inflammatory signal in systemic autoimmunity mental role is highly dependent on the timing. Indeed, Ab- is type 1 IFN. Patients with systemic lupus erythematosus mediated depletion of pDCs at the onset of EAE exacerbates display an increased IFN gene signature (129, 130), and pDCs the pathophysiological response (157, 158). Similarly, in mice from these patients are more prone to induce pathogenic lacking MHC-II expression in pDCs, EAE severity was in- T cell responses (131, 132). The pathogenic role of type 1 creased and this was linked to a decrease in Treg proliferation, IFN in other autoimmune diseases is less clear, but it may also suggesting that pDCs contribute to immune tolerance by ac- contribute to these pathologies (133, 134). Prior to islet in- tivating Tregs (97). In contrast, pDC depletion during the filtration by autoreactive T cells, autoimmune-prone NOD priming phase decreases the onset and the severity of the disease mice already exhibit increased type 1 IFN and IFN response (158). Therefore, the context and timing in which DCs genes in the islets, and blocking type 1 IFN at this early stage transmit signals to other immune cells determine whether they inhibits diabetes pathogenesis (135–137). This suggests that will contribute to exacerbating the immunopathology or confer type 1 IFN is critical for the initial break in tolerance. immune tolerance. However, the role of chronic innate signals on DCs at later Maintenance of immune tolerance is also relevant in the disease stages is less clear. Despite increased chronic type 1 context of GVHD where pathogenic alloimmunity develops. IFN exposure, DCs from older prediabetic NOD mice dis- Depletion of DCs in the GVHD setting via the utilization play impaired type 1 IFN responses due in part to down- of CD11c-DTR bone marrow decreases the expansion of 2228 BRIEF REVIEWS: DENDRITIC CELLS IN IMMUNE TOLERANCE allogenic T cells, suggesting that donor DCs contribute to the + 2 Disclosures pathogenesis (159). Specifically, the CD103 CD11b DC The authors have no financial conflicts of interest. subset is sufficient to cause GVHD, as exemplified in Irf4- deficient bone marrow chimeras (159). However, pDCs were References shown to protect against GVHD by inducing Tregs (101). 1. Steinman, R. M. 1991. The dendritic cell system and its role in immunogenicity. MHC-II–deficient DCs are also linked with a reduction in Annu. Rev. Immunol. 9: 271–296. 2. Salem, S., D. Langlais, F. Lefebvre, G. Bourque, V. Bigley, M. Haniffa, Tregs in the context of GVHD (160). These findings support J. L. Casanova, D. Burk, A. Berghuis, K. M. 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